ABSTRACT The goal of this U44 proposal is to develop and test CranialProgrammer, an image-guided programming tool for 2D/3D mapping of disease-related neural signals over patient and device data for more efficient and effective programming of directional deep brain stimulation (DBS) systems. DBS is an established treatment for advanced, refractory movement disorders used in over 150,000 patients. However, many patients receive inadequate symptom control due to poorly placed DBS leads, current spread to unwanted structures, or non- optimized stimulation parameters; all of which are caused or exacerbated by the use of conventional 4-contact ?omnidirectional? leads. Recent advances show directional leads, i.e. 8-contact leads with circumferentially segmented electrodes in a 1-3-3-1 configuration, can alleviate limitations by steering current toward pathological regions of interest (ROIs) and away from unwanted structures. This can increase DBS efficacy and widen therapeutic windows (TW) up to 111%. However, the greater numbers of contacts on directional leads adds more possible monopolar and bipolar configurations, especially when combined with independent current sources that distribute current unevenly across contacts. Although these advancements offer unprecedented therapeutic control, the time needed to explore all possible parameters is overwhelming. Tools are needed to narrow the neurologist's focus for identification of correct programming settings on directional DBS leads. Recent studies show features of basal ganglia local field potentials (LFPs) are strongly correlated to Parkinson's disease (PD) symptoms, indicating LFPs can be used to guide DBS toward the pathological ROI. Therefore, a new programming method using LFP-maps could harness directional lead benefits by offsetting their added complexity. To this end, we propose CranialProgrammer, an intuitive, LFP- based DBS programming software module to facilitate contact selection on directional leads. It will interface with Nexeon's SynapseTM DBS System, which has unprecedented capabilities for directional stimulation and directional LFP sensing in DBS implants. CranialProgrammer will allow visualization of disease-related LFPs collected by the Synapse and mapped over multimodal patient data, including brain MRI, CT images of lead implants, microelectrode recordings, and motor scores. It will provide clinicians with auto-generated, easily- navigable, data-rich patient images to select the best contact for directional DBS more efficiently and effectively. In Phase I we will automate CranialProgrammer to perform data entry, analysis and spatial mapping of LFPs on multi-modal datasets via the Nexeon External Research System (ERS) (Aim 1). We will perform verification and validation testing (Aim 2), and get IRB approval for a clinical study (Aim 3). In Phase II we will validate efficacy of map-based selection compared to clinical selection on PD patients (N=10) with the chronically implanted Synapse device. The Criteria for Success is ?80% of patients exhibit either a clinically meaningful increase in therapeutic window (>16%) or efficacy (>2.3-pt in UPDRS-III) when programmed with CranialProgrammer.